Plasmodium falciparum is the causative agent responsible for the most severe form of human malaria, a disease that kills more than 800,000 people a year, mostly young children in Africa. These protozoan parasites invade and ultimately destroy circulating red blood cells (RBCs) of their host, leading to severe anemia and the frequently lethal syndromes of cerebral malaria and pregnancy associated malaria. Over the course of an infection, small sub-populations of parasites arise that have an altered antigenic phenotype, thus avoiding the antibody response of the host. This process is referred to as antigenic variation and is responsible for the persistent nature of the disease as well as the waves of parasitemia frequently observed in P. falciparum infections. Antigenic variation of P. falciparum infected RBCs results from switches in expression between individual members of the multi-copy var gene family. Each var gene encodes a different form of a protein called PfEMP1. This protein is placed on the surface of the infected RBCs and mediates adhesion to specific receptors found on the endothelial surfaces of the blood vessel walls of the infected individual. This adhesion is responsible for many of the disease manifestations of infection with P. falciparum, including both cerebral malaria and pregnancy associated malaria. Only a single var gene is expressed at a time by any given parasite, thus determining the both the antigenic phenotype of the infected cells as well as their adhesive properties. Therefore var gene expression is at the heart of both antigenic variation and virulence of malaria infections. The long-term objectives of this project are to understand the molecular mechanisms that regulate var gene expression and antigenic variation by malaria parasites. Previous work identified a unique regulatory element found in all var genes that is necessary for proper regulation of each var gene. The specific aims of the project are designed to determine exactly how this element exerts its influence on the gene family and how switching between var genes is coordinated. Aim 1 investigates the recruitment of a specific histone modifier called PfSET2 to var genes through direct interactions with RNA pol II during the transcription of noncoding RNAs. The second aim investigates the role of an unusual var gene in coordinating the switching process. Collectively, this project will contribute to the ongoing effort to develop methods to disrupt the process of antigenic variation and thereby shorten the length of an infection and reduce its severity.